Decreased insulin action, impaired insulin secretion and increased adiposity are important risk factors for development of type 2 diabetes. These risk factors are present even when individuals have both normal fasting and two hour glucose concentrations indicating a very early role for decreased insulin secretion in the development of type 2 diabetes. In addition, the inability to suppress lipid oxidation (an example of metabolic inflexibility) is associated with worsening glucose tolerance status, and predicts decline in insulin action and development of type 2 diabetes. [unreadable] [unreadable] Offspring of diabetic mothers are also at high risk for type 2 diabetes at early ages, likely via an in utero effect on insulin secretion. A recent study demonstrated that insulin responses to a mixed meal were lower in offspring of diabetic compared to non-diabetic pregnancies, further supporting this hypothesis.[unreadable] [unreadable] Previous predictors of weight gain based on this study have included relatively lower energy expenditure, higher respiratory quotient, and higher insulin mediated glucose uptake. In addition, lower glucose during an oral glucose tolerance test individuals with normal glucose tolerance also predicts weight gain, indicating a role for glucose sensing in satiety. This has been confirmed in a shorter-term study during which individuals were followed during an inpatient admission. Investigation into the role of hormones on energy expenditure has found that glucagon like peptide 1 (GLP-1) and free T3 (but not free T4) is positively associated with resting and sleeping metabolic rate, respectively. Furthermore lower free T3 (but not free T4) is also associated with weight gain. This indicates a role for deiodinases (particularly deiodinase 2) in the regulation of energy expenditure and weight gain.